Highlights from Recent Cancer Literature
Journal: Cancer Research (2014)

Schramek D, Sendoel A, Segal JP, Beronja S, Heller E, Oristian D, et al. Direct in vivo RNAi screen unveils myosin IIa as a tumor suppressor of squamous cell carcinomas. Science 2014;343:309–13.Schramek and colleagues address the relevance of passenger mutations to oncogenesis by utilizing ultrasound-guided lentiviral shRNA delivery to infect single-layer embryonic day-9.5 ectoderm. Pools of shRNA targeting genes relevant to head and neck squamous cell carcinomas (HNSCC) were introduced into the ectoderm of mice sensitized to HNSCC development; all showed increased numbers of HNSCCs. Forty percent of the tumors were enriched for shRNAs against Myh9, nonmuscle myosin IIa. Cells lacking Myh9 expression were defective for biologic endpoints associated with the ATPase domain of MYH9, acting independently of actin polymerization. These findings suggest that MYH9 suppresses tumors by stabilizing p53 in the nucleus.Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillère R, Hannani D, et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 2013;342:971–6.Iida N, Dzutsev A, Stewart CA, Smith L, Bouladoux N, Weingarten RA, et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironmnent. Science 2013;342:967–70.Two recent studies published in Science suggest that commensal intestinal bacteria influence the outcome of cancer treatment. Using mouse transplantable cancer models, Viaud and colleagues showed that efficacy of cyclophosphamide depends on “normal healthy” gut microbiota, whereas Iida and colleagues report that subcutaneous mouse tumors did not respond to platinum chemotherapy or immunotherapy after antibiotic therapy. In both cases, gut bacteria normally prime the tumor-associated leukocytes to a more effective immune response after therapy. Antibiotics are used prophylactically in some cancer patients. These data suggest that manipulation of the gut microbiome influences outcome, and that commensal microbes are critical when developing or assessing treatments. After all, 90% of our cells are not human.Fantozzi A, Gruber DC, Pisarsky L, Heck C, Kunita A, Yilmaz M, et al. VEGF-mediated angiogenesis links EMT-induced cancer stemness to tumor initiation. Cancer Res; Published OnlineFirst January 10, 2014; doi:10.1158/0008-5472.CAN-13-1641.Epithelial-to-mesenchymal transition (EMT) enables invasion, metastases, and cancer stem cells. To clarify molecular mechanisms, Fantozzi and colleagues demonstrated that EMT upregulated expression of VEGFA and increased angiogenesis, enhancing tumorigenicity of murine breast cancer cells. Whereas expression of VEGFA was necessary for increased tumor initiation in cells that had undergone EMT, VEGFA itself was unable to support tumor formation of epithelial breast cancer cells before EMT, indicating the requirement for additional factors induced during EMT. The authors propose that the connecting mechanism between cancer cell stemness and tumor initiation might be cancer stem cells with EMT-induced, VEGFA-mediated angiogenesis.White AC, Khuu JK, Dang CY, Hu J, Tran KV, Liu A, Gomez S, Zhang Z, Yi R, Scumpia P, Grigorian M, Lowry WE. Stem cell quiescence acts as a tumour suppressor in squamous tumours. Nat Cell Biol 2014;16:99–107.How does oncogenic signaling take place in quiescent adult stem cells? White and colleagues show that hair follicle stem cells (HFSC) exist in two states: telogen when quiescent, and anagen when proliferative. HFSCs are insulated from oncogenic signaling during quiescence (telogen) and can be RasG12D transformed only when activated into anagen. During quiescence, PTEN activation and loss/inhibition of AKT, CREB, and JUN made HFSCs refractory to Ras. Pten loss downregulated genes that induced telogen (i.e., FGF18 and BMP2/4/6), but did not affect genes that induced anagen. Thus, loss of Pten created a telogen phase sensitive to tumor initiation. These data suggest that quiescence is dominant over oncogenic signaling, and that specific cues may reprogram malignant cells into quiescence despite powerful oncogenes.Lubanska D, Market-Velker BA, Decarvalho AC, Mikkelsen T, Fidalgo da Silva E, Porter LA. The cyclin-like protein Spy1 regulates growth and division characteristics of the CD133+ population in human glioma. Cancer Cell 2014;25:64–76.To characterize mechanisms related to stemness in glioma-initiating cells (GIC), Lubanska and colleagues studied the cyclin-like protein, SPY1 (SPDYA). Amplification of SPY1 was correlated with poor prognosis in patients. Knockdown caused decreased proliferation, loss of GIC markers, increased expression of neuronal markers, and increased asymmetric division of GICs, whereas overexpression stabilized a stem-like state in neural stem cells. Interestingly, while loss of SPY1 blocked CDK2, knockdown of the CDK2 regulator cyclin E did not similarly affect stemness or asymmetric division. Overall, these findings demonstrate a role for a specific cell-cycle regulatory protein in balancing cell division and stemness in glioma.Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.